PROJECT SUMMARY The Agency for Toxic Substances and Disease Registry (ATSDR) has identified the need for additional epidemiological research on the health effects of poly- and perfluoroalkyl substances (PFAS) exposures, particularly from contaminated drinking water and for compounds even less studied than perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), such as perfluorononanoic acid (PFNA). The highest levels of PFNA contamination in public and private water wells recorded anywhere in the world were found in Paulsboro and West Deptford New Jersey, where measurable levels of other poly- and perfluoroalkyl substances (PFAS) were also detected. Contaminated drinking water is an important and growing source of exposure to PFNA and other PFAS, and it estimated that millions of adults and children are exposed to PFAS in drinking water. Associations between serum PFAS levels in the general population and a wide range of health effects have been reported, but relatively little is known about health effects from consuming water contaminated with PFAS. There is a critical need to better understand the health hazards and risks of PFNA and other PFAS in drinking water. The main objective of this proposal is to evaluate associations between health outcomes and multiple estimates of exposure to PFNA and other PFAS among members of these communities and the other study sites in a multi-site study. A number of hypotheses will be tested, including that exposure to PFNA and other PFAS are associated with blood lipid levels, renal function and kidney disease, thyroid hormones and disease, liver function and disease, glycemic parameters and diabetes, and immune response and function in both children and adults. Additional hypothesized effects to be studied include differences in sex hormones and sexual maturation, vaccine response, and neurobehavioral outcomes in children, as well as cardiovascular disease, osteoarthritis and osteoporosis, endometriosis, and autoimmune disease in adults. The rationale for these multiple cross-sectional analyses is to test hypotheses for which there is sufficient statistical power based on prior reports, to develop new hypotheses, and to build a foundation for future knowledge generation with members of these communities. As part of the multi-site study with a target enrollment of 6,000 adults and 2000 children, 1,000 adults and 350 children from the Paulsboro and West Deptford municipalities who consumed water from wells contaminated with PFNA and other PFAS will be enrolled. Assessment of exposure to PFAS will be based on blood concentrations of PFAS and drinking water exposure reconstruction and PBPK modeling of internal exposure, including development of novel models for PFNA. Estimation of associations between health outcomes and measured and modeled exposure to PFAS will be done for this site and across sites of this multi-site study. The proposed project is relevant to public health, because our results will strengthen the evidence basis for making decisions about policies and actions to protect human health when people may be exposed to PFAS from drinking water.